Kohro Yuta, Brown Craig E, Trang Tuan
Faculty of Veterinary Medicine, University of Calgary, Calgary, AB, Canada.
Department of Physiology and Pharmacology, Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada.
Mol Brain. 2025 Jul 7;18(1):59. doi: 10.1186/s13041-025-01231-9.
Passage of molecules across the central nervous system is tightly regulated by the blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB), which restrict entry of many substances, including opioid medications. Here, we examined the effects of opioid withdrawal on BBB and BSCB integrity by measuring extravascular levels of peripherally injected dyes - Evans Blue (high molecular weight) and sodium fluorescein (NaFl, low molecular weight) - in the brain and spinal cord. In morphine-dependent male and female mice, repeated naloxone challenge induced robust withdrawal behaviors concomitant with region specific dye extravasation. In a fixed dose morphine paradigm, Evans Blue extravasation was highest within the cortex, hippocampus, cerebellum, and brainstem (pons and medulla) in male mice, and in the hypothalamus in female mice. By contrast, NaFl extravasation remained unchanged in both sexes. In an escalating dose morphine paradigm, Evans Blue extravasation was most prominent in the brainstem (pons and medulla) of both sexes, as well as in the lumbar of male mice and cervical spinal cord of female mice. NaFl extravasation in these regions was unchanged in male but reduced in female mice. These findings suggest that repeated opioid withdrawal alters permeability of the BBB and BSCB in discrete regions of the brain and spinal cord.
分子穿过中枢神经系统受到血脑屏障（BBB）和血脊髓屏障（BSCB）的严格调控，这些屏障限制了包括阿片类药物在内的许多物质的进入。在此，我们通过测量外周注射染料（伊文思蓝（高分子量）和荧光素钠（NaFl，低分子量））在脑和脊髓中的血管外水平，研究了阿片类药物戒断对BBB和BSCB完整性的影响。在吗啡依赖的雄性和雌性小鼠中，反复给予纳洛酮激发会诱导强烈的戒断行为，并伴随区域特异性染料外渗。在固定剂量吗啡范式中，雄性小鼠的皮质、海马体、小脑和脑干（脑桥和延髓）以及雌性小鼠的下丘脑内伊文思蓝外渗最高。相比之下，两性的NaFl外渗均保持不变。在递增剂量吗啡范式中，两性的脑干（脑桥和延髓）以及雄性小鼠的腰椎和雌性小鼠的颈脊髓中伊文思蓝外渗最为明显。这些区域的NaFl外渗在雄性小鼠中不变，但在雌性小鼠中减少。这些发现表明，反复的阿片类药物戒断会改变脑和脊髓离散区域中BBB和BSCB的通透性。
